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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • C07D495/04—Ortho-condensed systems

Definitions

• the present invention relates to compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents. More particularly, this invention concerns (1) certain inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) that include a pyridine containing nucleus attached by means of a linker to an HMG-binding domain sidechain, (2) pharmaceutical compositions containing such compounds and (3) a method of lowering blood serum cholesterol levels and modulating blood serum lipid levels employing such pharmaceutical compositions.
• HMG-CoA reductase 3-hydroxy-3-methylglutaryl-coenzyme A reductase
• Am is a binding domain sidechain
• X is a linker
• R 1 and R 2 are the same or different and are each independently selected from
• R J is selected from i) hydrogen, ii) lower alkyl, iii) aryl, iv) cycloalkyl, v) alkoxy, vi) aralkyl, vii) aralkoxy, viii alkenyl, ix) cycloalkenyl, x) halo-substituted alkyl, xi) adamantyl, and xii) heterocyclo (e.g., thienyl, benzodioxolyl);
• R is selected from i) hydrogen, ii) lower alkyl, iii) aryl, iv) cycloalkyl, v) alkoxy, vi) aralkyl, vii) aralkoxy, viii) alkenyl, ix) cycloalkenyl, x) adamantyl, xi) halogen, xii) halo-substituted alkyl (e.g., trifluoromethyl) , and (xiii) heterocyclo (e.g., thienyl, benzodioxolyl); or R 3 and R 4 taken together can be
• R 6 is hydrogen or lower alkyl
• R 8 is hydrogen, lower alkyl, alkali metal, or alkaline earth metal; n is 0 or 1; p is 3, 4 or 5; q is 0, 1, 2, or 3; and r is 0, 1, 2, or 3.
• (Am) is an HMG-binding domain sidechain having a dihydroxy or a phosphinic acid function.
• the phosphinic (or phosphonic when X is CH 2 -0-) acid HMG-binding domain sidechain (A x ) is
• R 5 and R 7 are independently selected from hydrogen, lower alkyl, alkali metal ion and alkaline earth metal ion; and R 6 is hydrogen or lower alkyl.
• the dihydroxy acid binding domain sidechain (A 2 is
• R 6 is hydrogen or lower alkyl
• R 8 is hydrogen or lower alkyl in free acid form or in the form of a physiologically acceptable and hydrolyzable ester or ⁇ lactone thereof (i.e., when Am is
• R 8 can be alkali metal ion or alkaline earth metal ion.
• certain pyridine-containing compounds that are potent inhibitors of cholesterol biosynthesis by virtue of their ability to inhibit the enzyme 3-methyl-glutaryl- coenzyme A reductase (HMG-CoA reductase) .
• the present invention provides compounds of the formula
• X is 0, S or NR 7 ;
• n 0 or 1
• Ri and R 2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
• R 3 is H, or lower alkyl;
• R is H, halogen, CF 3 , hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
• R 7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl;
• R 8 is H or lower alkyl
• R 9 and R i0 are the same or different and are independently selected from H or alkyl, or where at least one of R 9 and R ⁇ 0 is alkyl, Rg and Rio may be taken together with the carbon or carbons to which they are attached to form a 3 to 7 membered carbocyclic ring, which may include a spirocyclic ring; and f represents a single bond or a double bond (which may be cis or trans) ; and including pharmaceutically acceptable salts thereof where R 3 is H, esters thereof, prodrug esters thereof, and all stereoisomers thereof.
• the Z group will be in form of a free acid, a physiologically acceptable and hydrolyzable ester or ⁇ lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt.
• Ri and R 2 are independently selected from alkyl, cycloalkyl and aryl;
• R is H, alkyl or halogen; X is 0; and n is o.
• Ri is aryl (especially substituted aryl as defined hereinafter) ;
• R 2 is alkyl or cycloalkyl
• R 4 is H
• R 9 and Rio are H; X is 0; n is o; and lX
• Ri is substituted aryl, preferably 4-fluorophenyl, 4-fluoro-3-methylphenyl or 3, 5-dimethylphenyl;
• R 2 is alkyl or cycloalkyl, preferably isopropyl, t- butyl or cyclopropyl;
• R is H
• R 5 and Re are the same or different and independently selected from H, halogen and/or alkyl (preferably 4-fluoro, 4-fluoro-3-methyl or 3, 5-dimethyl) ; and R 2 is alkyl or cycloalkyl, preferably isopropyl, t- butyl or cyclopropyl.
• the present invention provides pharmaceutical compositions, useful as hypolipidemic or hypocholesterolemic agents, or hypotriglyceridemic agents, or anti-Alzheimer's agents, or anti-osteoporosis agents as we ⁇ l as other uses as described herein, comprising a hypolipidemic or hypocholesterolemic or hypotriglyceridemic or anti-Alzheimer's disease or anti- osteoporosis amount, or other therapeutically effective amount (depending upon use) of a compound of formula I in accordance with this invention, in combination with a pharmaceutically acceptable carrier.
• the present invention provides a method of inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels such as lowering LDL cholesterol and/or increasing HDL cholesterol, or treating dyslipidemia, mixed dyslipidemia, hyperlipidemia, hypercholesterolemia, hypo ⁇ -lipoproteinemia, LDL Pattern B, LDL Pattern A, hyperlipoproteinemia or hypertriglyceridemia, and other aberrations of apolipoprotein B metabolism, or reducing levels of Lp(a), or treating or preventing other cholesterol-related diseases, or treating or preventing or reversing progression of atherosclerosis, or preventing or treating Alzheimer's disease, or preventing or treating osteoporosis and/or osteopenia, or reducing inflammatory markers such as C-reactive protein, or preventing or treating low grade vascular inflammation, or preventing or treating stroke, or preventing or treating dementia, or preventing and treating coronary heart disease (including primary and secondary prevention of myocardial infarction) , or preventing or treating stable and unstable
• a method for preventing or treating diabetes, especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction, wherein a therapeutically effective amount of a compound of structure I is administered to a patient in need of treatment.
• diabetes especially Type 2 diabetes, and related diseases such as insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction
• a method for preventing and treating malignant lesions (such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast) , premalignant lesions (such as fibroadenoma of the breast and prostatic intraepithelial neoplasia (PIN) , gastrointestinal malignencies, liposarcomas and various other epithelial tumors (including breast, prostate, colon, ovarian, gastric and lung) , cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn's disease, gastric ulceritis, and gallstones, and HIV infection, other infectious diseases, drug-induced lipodystrophy, and proliferative diseases such as psoriasis, wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.
• malignant lesions such as ductal carcinoma in situ of the breast and lobular carcinoma in situ of the breast
• premalignant lesions such as fibroadenoma of the
• a method for improving coagulation homeostasis including reducing PAI-1 activity, reducing fibrinogen, and/or reducing platelet aggregation, and/or improving endothelial function, wherein a therapeutically effective amount of a compound of structure I is administered to a patient in need of treatment.
• a method for treating cholesterol related diseases, diabetes and related diseases, cardiovascular diseases, cerebrovascular diseases as defined above and hereinafter and other diseases as set out above, wherein a therapeutically effective amount of a combination of a compound of structure I and a hypolipidemic agent, and/or lipid modulating agent and/or antidiabetic agent and/or cardiovascular agent, cerebrovascular agent, and/or other type of therapeutic agent, is administered to a patient in need of treatment.
• the compound of structure I will be employed in a weight ratio to the other therapeutic agent (depending upon its mode of operation) within the range from about 0.01:1 to about 500:1, preferably from about 0.5:1 to about 100:1.
• compounds useful in inhibiting the enzyme HMG- CoA reductase which inhibitors are useful as hypocholesterolemic agents, dyslipidemic agents, hypolipidemic agents, hypotriglyceridemic agents, anti- Alzheimer's disease agents, and antiosteoporosis agents as well as other uses as described herein.
• coronary events refers to myocardial infarction, myocardial revascularization procedures, angina, cardiovascular death and acute coronary syndrome.
• cardiac diseases or events refers to atherosclerosis of the coronary arteries, myocardial infarction, including primary MI and secondary MI, recurrent myocardial infarction, angina pectoris (including stable and unstable angina) , congestive heart failure, and sudden cardiac death.
• cardiac diseases or events refers to cerebral infarction or stroke (caused by vessel blockage or hemmorage) , or transient ischemia attack (TIA) , syncope, atherosclerosis of the intracranial and/or extracranial arteries, and the like.
• cholesterol-related diseases refers to diseases involving elevated levels of LDL cholesterol, diseases involving regulation of LDL receptors, diseases involving reduced levels of HDL cholesterol, dyslipidemia, hyperlipidemia, elevated LDL Pattern B, elevated LDL Pattern A, hypercholesterolemia, hypo ⁇ -lipoproteinemia (low HDL cholesterol syndrome) , hyperlipoproteinemia, elevated Lp(a) levels, hypertriglyceridemia, other aberrations of apolipoprotein B metabolism, heterozygous familial, presumed familial combined and non-familial (non-FH) forms of primary hypercholesterolemia (including Frederickson Types Ila and lib) , cholesterol ester storage disease, and cholesterol ester transfer protein disease, and related diseases.
• diseases involving elevated levels of LDL cholesterol diseases involving regulation of LDL receptors, diseases involving reduced levels of HDL cholesterol, dyslipidemia, hyperlipidemia, elevated LDL Pattern B, elevated LDL Pattern A, hypercholesterolemia, hypo ⁇ -lipoproteinemia (low HDL cholesterol syndrome)
• Dysmetabolic Syndrome includes hyperglycemia and/or prediabetic insulin resistance syndrome, and is characterized by an initial insulin resistant state generating hyperinsulinemia, dyslipidemia, and impaired glucose tolerance, which can progress to Type II diabetes, characterized by hyperglycemia, which can progress to diabetic complications.
• diabetes and related diseases refers to Type II diabetes, Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia, Syndrome X, dysmetabolic syndrome, diabetic complications and hyperinsulinemia .
• diabetes complications include retinopathy, neuropathy and nephropathy, and other known complications of diabetes.
• other type(s) of therapeutic agents refers to one or more antidiabetic agents (other than compounds of formula I), one or more anti- obesity agents, and/or one or more lipid-lowering agents, one or more lipid modulating agents (including anti- atherosclerosis agents) , other types of anti- atherosclerosis agents, and/or one or more antiplatelet agents, one or more agents for treating hypertension, one or more anti-cancer drugs, one or more agents for treating arthritis, one or more anti-osteoporosis agents, one or more anti-obesity agents, one or more agents for treating immuno odulatory diseases, and/or one or more agents for treating anorexia nervosa.
• lipid-modulating agent refers to agents which lower LDL and/or raise HDL and/or lower triglycerides and/or lower total cholesterol and/or other known mechanisms for therapeutically treating lipid disorders.
• anti-atherosclerosis agents refers to conventional anti- atherosclerosis agents including lipoxygenase inhibitors, ACAT inhibitors, antioxidants, PPAR ⁇ agonists, phospholipase inhibitors including PLA-2 inhibitors and/or other known anti-atherosclerotic agents.
• salts refer to basic salts formed with inorganic and organic bases.
• Such salts include ammonium salts; alkali metal salts, such as lithium, sodium and potassium salts (which are preferred) ; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as amine like salts (e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts) ; and salts with amino acids like arginine, lysine and the like; and zwitterions, the so-called “inner salts”.
• amine like salts e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, and hydrabamine salts
• Nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
• pharmaceutically acceptable “salt” and “salts” also includes acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid such as HCl or HBr, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or
• lower alkyl as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4-dimethylpentyl, octyl, 2,2, 4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, Cl or I or CF3, alkyl, alkoxy, aryl, aryloxy, aryl (aryl
• cycloalkyl as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containing a total of 3 to 20 carbons forming the ring, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl ,
• any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, heteroaryl, cycloheteroalkyl, amino, alkylamino, nitro, cyano, thiol and/or alkylthio and/or any of the substituents for alkyl.
• substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, heteroaryl, cycloheteroalkyl, amino, alkylamino, nitro, cyano, thiol
• cycloalkenyl as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 3 to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.
• exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl.
• alkanoyl as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
• lower alkenyl or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,
• lower alkynyl or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3- pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, al
• arylalkenyl and arylalkynyl as used alone or as part of another group refer to alkenyl and alkynyl groups as described above having an aryl substituent.
• alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed “alkylene” groups and may optionally be substituted with 1 or 2 substituents as defined above for “alkyl”, such as, for example, alkyl, halo, hydroxy, alkoxy and/or cycloalkyl.
• alkenyl groups as defined above and alkynyl groups as defined above, respectively have single bonds for attachment at two different carbon atoms, they are termed “alkenylene groups” and “alkynylene groups”, respectively, and may optionally be substituted with 1 or 2 substituents as defined above for “alkenyl” and “alkynyl” .
• halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred.
• metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
• aryl refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example
• lower alkoxy as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
• substituted amino refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid and/or any of the substituents for alkyl as set out above.
• amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1- piperidinyl, 1-azepinyl, 4-morpholinyl, 4- thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-pi ⁇ erazinyl, 4- arylalkyl-1-piperazinyl, 4-diarylalkyl-l-piperazinyl, 1- pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
• lower alkylthio alkylthio
• arylthio arylthio
• aralkylthio as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
• lower alkylamino as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
• acyl as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a
• acyl groups include any of the R 1 groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.
• cycloheteroalkyl refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) r (where r is 1, 2 or 3) , such as
• any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
• heteroaryl refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl) , and includes possible N- oxides.
• the heteroaryl group may optionally include 1 to 4 substituents such as any of the substituents set out above for alkyl. Examples of heteroaryl groups include the following:
• cycloheteroalkylalkyl refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH 2 ) r chain.
• heteroarylalkyl or “heteroarylalkenyl” as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a -(CH 2 ) r - chain, alkylene or alkenylene as defined above.
• polyhaloalkyl refers to an "alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
• polyhaloalkoxy refers to an "alkoxy” or "alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 0, CF 3 0 or CF 3 CF 2 CH 2 O.
• All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
• the compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one or the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof.
• the processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
• prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like.
• prodrug esters which are known in the art for carboxylic and phosphorus acid esters such as methyl, ethyl, benzyl and the like. Examples of such prodrug esters include
• Suitable prodrug esters include
• R a can be H, alkyl (such as methyl or t-butyl) , arylalkyl (such as benzyl) or aryl (such as phenyl) ;
• R d is H, alkyl, halogen or alkoxy,
• R e is alkyl, aryl, arylalkyl or alkoxyl, and ni is 0, 1 or 2.
• the compounds of structure I may form a pharmaceutically acceptable salt such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L) , ethylenediamine, t-butylamine, t- ⁇ ctylamine, tris- (hydroxymethyl) aminomethane (TRIS) , N-methyl glucosamine (NMG) , triethanolamine and dehydroabietylamine.
• a pharmaceutically acceptable salt such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L) , ethylenediamine, t-butylamine, t- ⁇ ctylamine, tris- (hydroxymethyl) aminomethane (TRI
• aldehyde 2 under standard conditions (e.g. HOAc, piperidine, toluene, reflux) affords the corresponding adduct 3.
• Base induced 1,4- addition of ketone 4 e.g. LiN(TMS) 2 in THF or EtONa in EtOH
• provides the adduct 5 usually as a mixture of diastereomers .
• Conversion of the 1,5-diketone 5 to the pyridyl ester 6 may be effected by treatment with an ammonia source (such as NH 4 OAc) in the presence of an oxidant (such as Cu(OAc)2 or oxygen) in a suitable solvent (such as refluxing HOAc) , or by reaction of 5 with hydroxylamine hydrochloride in HOAc with heat .
• an ammonia source such as NH 4 OAc
• an oxidant such as Cu(OAc)2 or oxygen
• a suitable solvent such as refluxing HOAc
• the ester functionality of 6 can be reduced by standard methods (LiAlH 4 , DIBAL, LiBH to give alcohol 7 which can subsequently be converted to the corresponding halide 8 (e.g. PBr 3 in CH 2 C1 2 , CBr 4 /PPh 3 in CH 3 CN or P0C1 3 ) .
• Conversion of halide 8 to the phosphorus compound 9 where W is Ph or alkyl is effected by treatment of 8 with W 2 POEt in toluene.
• Conversion of halide 8 to compound 9 where W is OR may be effected by the reaction of 8 with HOP (OR) 2/base/THF or by Arbuzov reaction with P(OR) 3 .
• Witting reaction between 9 and aldehyde 10 (aldehyde 10 has been previously described in US patent 5,686,433) may be effected under standard conditions with base (n-BuLi, LiN(TMS) 2 , LDA) in an appropriate solvent (THF, Et 2 0, toluene, DMPU) to afford the adduct 11.
• Treatment of 11 under acidic conditions effects the conversion of 11 to lactone la.
• Saponification of la to lb (where R 3 is alkali metal, or alkaline earth metal) can be effected by treatment of la with aqueous base or subsequently acidified to give lb where R 3 is H.
• la can be treated with an alcohol of the type R 3 OH under basic conditions to form the corresponding esters of lb.
• the saturated derivatives of compound I are obtained by catalytic (Pd/C, Pt/C, Pd(OH) 2 ) hydrogenation of 11, la, or lb to afford 12, Ic, or Id, respectively.
• Compound 12 may be converted to Ic and Id following the earlier described methods for the conversion of compound 11 to la and lb.
• lb 3 Treatment of lb 2 with oxidants such as m-CPBA or CF 3 C0 3 H in an appropriate solvent such as CH 2 C1 2 or HOAc affords N-oxide lb 3 .
• oxidants such as m-CPBA or CF 3 C0 3 H in an appropriate solvent such as CH 2 C1 2 or HOAc affords N-oxide lb 3 .
• Desilylation of lb 3 (TBAF/HOAc/THF or HF/CH 3 CN) gives lb 4 which may be saponified to lb 5 using aqueous solutions of a metal hydroxide in an appropriate solvent (e.g., MeOH, dioxane).
• a metal hydroxide e.g., MeOH, dioxane
• compound Id 1 may be oxidized and saponified, as described above, to provide compounds I wherein ⁇ is CH 2 CH 2 and n is 1 (e.g., compounds Id 2 and ID 3 ) as shown in Scheme 4.
• Scheme 5 depicts a preferred method for preparing the HMG CoA reductase inhibitor of formula I of the invention using the Julia-Kocienski olefination reaction employing 4-pyridyl carboxylaldehyde (18) and chiral sulfone (16) .
• the desired trans intermediate (19) is isolated in high yield and optical purity which is converted to the final product of the invention.
• the chiral sulfone (16) a key intermediate in the Julia-Kocienski step, is prepared in three steps starting from the commercially available Kaneka alcohol (12) via triflate (13) and sulfide intermediate (15) .
• triflate (13) treatment of commercially available chiral alcohol (12) with triflic anhydride and triethylamine in dichloromethane at low temperature (for example 0 to -30°C) affords triflate (13) .
• Other pyridine or amine bases may be employed.
• Triflate (13) (without being isolated) is carried onto the next step without further purification.
• a methylene chloride solution of triflate (13) is treated with 1-phenyl-lH- tetrazole-5-thiol (14) to provide the chiral sulfide (15) which is oxidized with hydrogen peroxide in the presence of catalytic ammonium heptamolybdate tetrahydrate to give crystalline sulfone (16) .
• Other oxidant such as m- chloro-p-benzoic acid (mCPBA) mey be employed.
• intermediates 6, 7, 8, 9, 11 and 12 are novel compounds and form part of the present invention. These compounds have the general structure
• the intermediates of the invention can have the following structures:
• Compounds 6, 7, 8, 9, 11 and/or 12 may include R 9 and Rio substituents.
• Compounds containing dihydroxy acid HMG-CoA binding domain side chains may be prepared in homochiral form, which is preferred, or may be prepared as racemic mixtures (3S*, 5R*) and may later be resolved to obtain the 3S, 5R isomer.
• the intermediates of the invention can have the following structures:
• Compounds containing dihydroxy acid HMG-CoA binding domain side chains may be prepared in homochiral form, which is preferred, or may be prepared as racemic mixtures (3S*, 5R*) and may later be resolved to obtain the 3S, 5R isomer.
• the compounds of the invention are inhibitors of 3- hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus are useful in inhibiting cholesterol biosynthesis and/or in lowering triglycerides, in a manner similar to atorvastatin, pravastatin, simvastatin, lovastatin, cerivastatin, visastatin (or rosuvastatin) (Astra Zeneca ZD4522) , fluvastatin, itavastatin (or pitavastatin) and the like.
• HMG-CoA 3- hydroxy-3-methyl-glutaryl coenzyme A reductase
• a further aspect of the present invention is a pharmaceutical composition containing at least one of the compounds of formula I of the present invention in association with a pharmaceutical vehicle or diluent.
• the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration.
• the compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations.
• Such dosage forms contain from 0.1 to 1500 mg of active compound per dosage, for use in the treatment.
• the dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient.
• the compounds of the present invention can be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol biosynthesis, such as pravastatin, lovastatin, simvastatin, visastatin (or rosuvastatin) , atorvastatin, cerivastatin, fluvastatin, itavastatin (or pitavastatin) , and the like, in mammalian species such as humans, dogs, cats and the like.
• the compounds of the invention may be administered in an amount from about 0.1 to 500 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 0.2 to 100 mg daily or in sustained release form.
• HMG CoA reductase inhibitors of formula I may be employed in combination with all therapeutic agents which are useful in combination with HMG CoA reductase inhibitors .
• the compounds of structure I may be used in combination with one or more hypolipidemic agents or lipid-lowering agents, or lipid agents, or lipid modulating agents, and/or one or more other types of therapeutic agents including antidiabetic agents, anti-obesity agents, antihypertensive agents, platelet aggregation inhibitors, anti-Alzheimer ' s agents, anti- dementia agents, anti-osteoporosis agents, and/or hormone replacement therapeutic agents, and/or other therapeutic agents, and/or other cardiovascular agents (including anti-anginal agents, anti-arrhythmic agents, anti- atherosclerosis agents, anti-inflammatory agents, anti- platelet agents, anti-heart failure agents) , anti-cancer agents, anti-infective agents, hormone replacement agents, growth hormone secretagogues , selective androgen receptor modulators, and/or other therapeutic agents which may be administered orally in the same dosage form or in a separate oral dosage form, or by injection.
• therapeutic agents including antidiabetic agents, anti-obe
• the hypolipidemic agent or lipid-lowering agent or other lipid agent or lipid modulating agent which may be optionally employed in combination with the compounds of formula I of the invention may include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, PPAR ⁇ agonists, PPAR dual ⁇ / ⁇ agonists, PPAR ⁇ agonists, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na + /bile acid cotransporter inhibitors, upregulators of LDL receptor activity, cholesteryl ester transfer protein inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof .
• MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983 and U.S. Application Serial No. 09/175,180 filed October 20, 1998, now U.S. Patent No. 5,962,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications .
• MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Patent Nos. 5,739,135 and 5,712,279, and U.S. Patent No. 5,760,246.
• the most preferred MTP inhibitor is 9- [4- [4- [[2- (2, 2,2-Trifluoroethoxy)benzoyl] amino] -1-piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-carboxamide
• the hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
• HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S.
• SC-45355 (a 3- substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2- hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2, 3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Patent No.
• phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
• the squalene synthetase inhibitors suitable for use herein include, but are not limited to, ⁇ -phosphono- sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl- methyDphosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Patent No. 4,871,721 and 4,924,024 and in Biller, S.A., Neuenschwander, K. , Ponpipom, M.M., and Poulter, CD., Current Pharmaceutical Design, 2, 1-40 (1996) .
• squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 2H, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ- PP) analogs as disclosed by Corey and Nolante , J. Am. Chem. Soc, 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R.W.
• hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No.
• bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex ® , Policexide ® ) and cholestagel (Sankyo/Geltex) , as well as lipostabil (Rhone-Poulenc) , Eisai E-5050 (an N-substituted ethanolamine derivative) , imanixil (HOE-402) , tetrahydrolipstatin (THL) , istigmastanylphos- phorylcholine (SPC, Roche) , aminocyclodextrin (Tanabe Seiyoku) , Ajinomoto AJ-814 (azulene derivative) , melinamide (Sumitomo) , Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives)
• cholestyramine colestipol and DEAE-
• the other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) such as disclosed in, Drugs of the Future 24, 9-15 (1999) , (Avasimibe) ; "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel) . (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein” , Ghiselli, Giancarlo, Cardiovasc. Drug Rev.
• the hypolipidemic agent may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly) .
• the hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough 1 s SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998) .
• the other lipid agent or lipid-modulating agent may be a cholesteryl transfer protein inhibitor (CETP) such as Pfizer' s CP-529,414 as well as those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795 as well as CETi-1 and JTT-705.
• CETP cholesteryl transfer protein inhibitor
• the hypolipidemic agent may be an ileal Na + /bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999) .
• the ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. Patent No. 5,447,954.
• the other lipid agent also includes a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterol absorption inhibitor such as disclosed in EP 675714; an HDL upregulator such as an LXR agonist, a PPAR ⁇ -agonist and/or an FXR agonist; an ⁇ -glucosidase inhibitor, an aldose reductase inhibitor and/or an LDL catabolism promoter such as disclosed in EP 1022272; a sodium-proton exchange inhibitor such as disclosed
• Patent No. 5,698,527 and GB 2304106 an anti-oxidant such as beta-carotene, ascorbic acid, ⁇ -tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin C and an antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed in WO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR ⁇ agonist for treating dyslipidemia; or a sterol regulating element binding protein-I (SREBP-1) as disclosed in WO 2000/050574, for example, a sphingolipid, such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof.
• SREBP-1 sterol regulating element binding protein-I
• Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, pitavastatin and rosuvastatin, as well as niacin and/or cholestagel.
• pravastatin pravastatin
• lovastatin simvastatin
• atorvastatin fluvastatin
• cerivastatin cerivastatin
• pitavastatin and rosuvastatin as well as niacin and/or cholestagel.
• the compounds of formula I of the invention will be employed in a weight ratio to the hypolipidemic agent (were present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.
• the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
• hypolipidemic agent or other lipid agent or lipid modulating agent will be as disclosed in the various patents and applications discussed above.
• the MTP inhibitor for oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one to four times daily.
• a preferred oral dosage form such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.
• an HMG CoA reductase inhibitor for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
• the squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg .
• a preferred oral dosage form such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 0.5 to about 80 mg, and more preferably from about 1 to about 40 mg.
• a preferred oral dosage form such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
• the anti-atherosclerotic agent includes a lipoxygenase inhibitor including a 15-lipoxygenase (15- LO) inhibitor such as benzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613, isothiazolones as disclosed in
• WO 96/38144 and 15-LO inhibitors as disclosed by Sendobry et al "Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15- lipoxygenase inhibitor lacking significant antioxidant properties," Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al, "15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease", Current Pharmaceutical Design, 1999, 5, 11-20.
• the compounds of formula I and the hypolipidemic agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
• compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
• the antidiabetic agent which may be optionally employed in combination with the HMG-CoA reductase inhibitor of formula I may be 1,2,3 or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR ⁇ agonists such as thiazolidinediones, PPAR ⁇ agonists (such as fibric acid derivatives) , PPAR ⁇ antagonists or agonists, aP2 inhibitors, PPAR / ⁇ dual agonists, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-1 (GLP-1) , and/or a PTP-1B inhibitor (protein
• the antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl .
• the compounds of structure I will be employed in a weight ratio to biguanide within the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1.
• the antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide) , glimepiride (disclosed in U.S. Patent No.
• the compounds of structure I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.02:1 to about 5:1.
• the oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No. 4,904,769) or miglitol (disclosed in U.S.
• Patent No. 4,639,436 which may be administered in the same or in a separate oral dosage forms .
• the compounds of structure I will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.
• the compounds of structure I may be employed in combination with a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner- Lambert's Rezulin ® , disclosed in U.S. Patent No. 4,572,912), rosiglitazone (SKB) , pioglitazone (Takeda) , Mitsubishi's MCC-555 (disclosed in U.S. Patent No.
• a PPAR ⁇ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner- Lambert's Rezulin ® , disclosed in U.S. Patent No. 4,572,912), rosiglitazone (SKB) , pioglitazone (
• Glaxo-Welcome ⁇ s GL-262570 englitazone (CP- 68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J) , JTT-501 (JPNT/P&U) , L-895645 (Merck), R-119702 (Sankyo/WL) , NN-2344 (Dr. Reddy/NN) , or YM-440 (Yamanouchi) , preferably rosiglitazone and pioglitazone.
• the compounds of structure I will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.
• the sulfonyl urea and PPAR ⁇ agonists in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with the compounds of structure I .
• the compounds of structure I may also be employed in combination with a antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) or mimetic such as GLP-1 (1-36) amide, GLP-1 (7-36) amide,
• GLP-1 (7-37) (as disclosed in U.S. Patent No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference)
• AC2993 Amylen
• LY-315902 (Lilly)
• GLP-1 7-37
• AC2993 Amylen
• LY-315902 Longer-like LY-315902
• metformin the sulfonyl ureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin (injectable, pulmonary, buccal, or oral) may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference (PDR) .
• metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.
• the PPAR anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
• present insulin and other anti-diabetic agents as set out above may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference .
• present GLP-1 peptides or mimetics may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Patent Nos. 5,346,701 (TheraTech) , 5,614,492 and 5,631,224 which are incorporated herein by reference.
• the antidiabetic agent or other lipid agent may also be a PPAR modulator such as a PPAR ⁇ / ⁇ dual agonist such as AR-H039242 (Astra/Zeneca) , GW-409544 (Glaxo- Wellcome) , KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation -
• PPAR modulator such as a PPAR ⁇ / ⁇ dual agonist such as AR-H039242 (Astra/Zeneca) , GW-409544 (Glaxo- Wellcome) , KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation -
• PPAR alpha Activated Receptor Alpha
• PPAR gamma Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47, 1841-1847 (1998), and in U.S. application Serial No. 09/664,598, filed September 18, 2000, (attorney file LA29) the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.
• the antidiabetic agent may be an SGLT2 inhibitor such as disclosed in U.S. application Serial No. 09/679,027, filed October 4, 2000 (attorney file LA49) , employing dosages as set out therein. Preferred are the compounds designated as preferred in the above application.
• the antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S. application Serial No. 09/391,053, filed September 7, 1999, and in U.S. application Serial No. 09/519,079, filed March 6, 2000 (attorney file LA27) , employing dosages as set out herein. Preferred are the compounds designated as preferred in the above application.
• the antidiabetic agent may be a DP4 inhibitor such as disclosed in application Serial No. 09/788,173, filed February 16, 2001 (attorney file LA50) , WO99/38501, W099/46272, W099/67279 (PROBIODRUG) , W099/67278 (PROBIODRUG), W099/61431 (PROBIODRUG), NVP-DPP728A (1- [ [ [2- [ (5-cyanopyridin-2-yl) amino] ethyl] amino] acetyl] -2- cyano- (S) -pyrrolidine) (Novartis) (preferred) as disclosed by Hughes et al, Biochemistry, 38(36), 11597- 11603, 1999, TSL-225 (tryptophyl-1, 2 , 3 , 4-tetrahydro- isoquinoline-3 -carboxylic acid (disclosed by Yamada et al, Bioorg.
• the meglitinide which may optionally be employed in combination with the compound of formula I of the invention may be repaglinide or Starlix® (Novartis) , nateglinide (Novartis) or KAD1229 (PF/Kissei) , with repaglinide being preferred.
• the antidiabetic compound may be a melanocortin receptor agonist such as a spiropiperidine as disclosed
• the HMG CoA reductase inhibitor of formula I will be employed in a weight ratio to the meglitinide, PPAR modulator such as a PPAR ⁇ agonist, PPAR ⁇ agonist, PPAR ⁇ agonits or antagonist, PPAR ⁇ / ⁇ dual agonist, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor or other antidiabetic agent within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.
• PPAR modulator such as a PPAR ⁇ agonist, PPAR ⁇ agonist, PPAR ⁇ agonits or antagonist, PPAR ⁇ / ⁇ dual agonist, aP2 inhibitor, DP4 inhibitor or SGLT2 inhibitor or other antidiabetic agent within the range from about 0.01:1 to about 100:1, preferably from about 0.05:1 to about 10:1.
• the other type of therapeutic agent which may be optionally employed with the HMG CoA reductase inhibitor of formula I may be 1, 2, 3 or more of an anti-obesity agent including a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroid receptor beta drug, a PTP-1B inhibitor, an anorectic agent, a PPAR modulator including PPAR ⁇ antagonists, PPAR ⁇ agonists, PPAR ⁇ antagonists, a CCKA agonist, a leptin inhibitor such as a leptin receptor activator, a neuropeptide Y antagonist, a melanocortin-4-receptor (MC4R) agonist, a fatty acid oxidation upregulator or inducer (such as Famoxin® Genset) .
• an anti-obesity agent including a beta 3 adrenergic agonist,
• the beta 3 adrenergic agonist which may be optionally employed in combination with a compound of formula I may be AJ9677 (Takeda/Dainippon) , L750355 (Merck) , or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648 being preferred.
• the neuropeptide Y antagonists which may be optionally employed in combination with a compound of formula I include those described in WO 0113917 (BMS) or in U.S. Patent No. 6,218,408 (Synaptic) and in WO 0114376 (Banyu) .
• the lipase inhibitor which may be optionally employed in combination with a compound of formula I may be orlistat or ATL-962 (Alizyme) , with orlistat being preferred.
• the serotonin (and dopoamine) reuptake inhibitor which may be optionally employed in combination with a compound of formula I may be sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron) , with sibutramine and topiramate being preferred.
• the thyroid receptor beta compound which may be optionally employed in combination with a compound of formula I may be a thyroid receptor ligand as disclosed in W097/21993 (U.
• the anorectic agent which may be optionally employed in combination with a compound of formula I may be dexamphetamine, phentermine, phenylpropanolamine or mazindol, with dexamphetamine being preferred.
• the CCKA agonists which may be employed herein include Glaxo-SmithKline' s GI-181,771 and Sanofi's SR146,131.
• the PTP-1B inhibitor which may be an anti-oesity and/or an antidiabetic agent include those disclosed in WO 99/585,521, WO 99/58518, WO 99/58522 and WO 99/61435.
• the anti-obesity agent employed may also be Pfizer' s P57 or CP-644,673 (licensed from Phytopharm) .
• the various anti-obesity agents described above may be employed in the same dosage form with the compound of formula I or in different dosage forms, in dosages and regimens as generally known in the art or in the PDR.
• the antihypertensive agents which may be employed in combination with the HMG CoA reductase inhibitors of the invention include ACE inhibitors, angiotensin II receptor antagonists, EP inhibitors such as candoxatril, NEP/ACE inhibitors, as well as calcium channel blockers (such as verapamil and amlodipine besylate) , T-channel calcium antagonists (such as mibefradil) , ⁇ -adrenergic blockers, diuretics, -adrenergic blockers (such as doxazosin mesylate and terazosin HC1) , dual action receptor antagonists (DARA) , heart failure drugs such as digoxin, and other types of antihypertensive agents.
• ACE inhibitors angiotensin II receptor antagonists
• EP inhibitors such as candoxatril
• NEP/ACE inhibitors as well as calcium channel blockers (such as verapamil and amlodipine besylate)
• the angiotensin converting enzyme inhibitor which may be employed herein includes those containing a mercapto (-S-) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1- [ (2S) -3-mercapto-2- ethylpropionyl] -L-proline, being preferred, and mercaptoacyl derivatives of substituted prolines such as any of those disclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.
• a mercapto (-S-) moiety such as substituted proline derivatives, such as any of those disclosed in U.S. Pat. No. 4,046,889 to Ondetti et al mentioned above, with captopril, that is, 1- [ (2S) -3-mercapto-2- ethylpropionyl] -L-proline,
• mercapto containing ACE inhibitors that may be employed herein include rentiapril (fentiapril, Santen) disclosed in Clin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril and YS980.
• angiotensin converting enzyme inhibitors which may be employed herein include any of those disclosed in U.S. Pat. No. 4,374,829 mentioned above, with N- (l-ethoxycarbonyl-3-phenylpropyl) -L-alanyl- L-proline, that is, enalapril, being preferred, any of the phosphonate substituted amino or imino acids or salts disclosed in U.S. Pat. No.
• ACE inhibitors include Beecham' s BRL 36,378 as disclosed in European Patent Application Nos. 80822 and 60668; Chugai's MC-838 disclosed in CA. 102:72588v and Jap. J. Pharmacol. 40:373 (1986); Ciba-Geigy' s CGS 14824 (3-([l- ethoxycarbonyl-3-phenyl- (IS) -propyl] amino) -2,3,4,5- tetrahydro-2-oxo-l- (3S) -benzazepine-1 acetic acid HC1) disclosed in U.K. Patent No.
• ACE inhibitors are captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.
• NEP/ACE inhibitors may also be employed herein in that they possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity.
• NEP/ACE inhibitors suitable for use herein include those disclosed in U.S. Pat. No.s. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688, U.S. Patent. No. 5,552,397, U.S.
• NEP/ACE inhibitors and dosages thereof which are designated as preferred in the above patents/applications which U.S. patents are incorporated herein by reference; most preferred are omapatrilat, gemopatrilat ( [S [ (R*, R*) ] -hexahydro-6- [ (2-mercapto-l-oxo- 3-phenylpropyl) amino] -2, 2-dimethyl-7-oxo-lH-azepine-l- acetic acid) and CGS 30440.
• the angiotensin II receptor antagonist (also referred to herein as angiotensin II antagonist or All antagonist) suitable for use herein includes, but is not limited to, irbesartan, losartan, valsartan, candesartan, tasosartan or eprosartan, with irbesartan, losartan or valsartan being preferred.
• a preferred oral dosage form, such as tablets or capsules, will contain the ACE inhibitor or All antagonist in an amount within the range from abut 0.1 to about 500 mg, preferably from about 5 to about 200 mg and more preferably from about 10 to about 150 mg.
• the ACE inhibitor, angiotensin II antagonist or NEP/ACE inhibitor will be employed in an amount within the range from about 0.005 mg/kg to about 10 g/kg and preferably from about 0.01 mg/kg to about 1 mg/kg.
• a drug is to be administered intravenously, it will be formulated in conventional vehicles, such as distilled water, saline, Ringer's solution or other conventional carriers . It will be appreciated that preferred dosages of ACE inhibitor and All antagonist will be as set out in the latest edition of the Physician's Desk Reference (PDR) .
• PDR Physician's Desk Reference
• Dual action receptor antagonists suitable for use herein include those disclosed in U.S. applications Serial No. 09/513,779, filed February 25, 2000, and Serial No. 09/604,322, filed June 26, 2000.
• antihypertensive agents suitable for use herein include omapatrilat (Vanlev®) , gemopatrilat, amlodipine besylate (Norvasc®) , prazosin
• HCl (Minipress®) , verapamil, nifedipine, diltiazem, felodipine, nisoldipine, isradipine, nicardipine, beta blockers such as nadolol, atenolol (Tenormin®) , sotalol, terazosin, doxazosin, carvedilol, and propranolol, and clonidine HCl (Catapres®) .
• Diuretics which may be employed in combination with compounds of formula I include hydrochlorothiazide, torasemide, furosemide, spironolactone, and indapamide.
• Antiplatelet agents which may be employed in combination with compounds of formula I of the invention include aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.
• antihypertensive agents, diuretics and antiplatelet drugs may be employed in amounts as indicated in the PDR. Ifetroban may be employed in amounts as set out in U.S. Patent No. 5,100,889.
• Anti-Alzheimer' s agents or anti-dementia agents suitable for use herein with the HMG CoA reductase inhibitors of the invention include tacrine HCl (Cognex®) and donepezil (Aricept®) , as well as ⁇ -secretase inhibitors, ⁇ -secretase inhibitors and/or antihypertensive agents. Dosages employed will be as set out in the PDR.
• Antiosteoporosis agents suitable for use herein in combination with the HMG CoA reductase inhibitors of the invention include parathyroid hormone or bisphosphonates, such as MK-217 (alendronate) (Fosamax®) as well as Ca receptor agonists and progestin receptor agonists. Dosages employed will be as set out in the PDR.
• the hormone replacement therapeutic agents where present, will be employed in dosages as set out in the latest edition of the PDR.
• examples of such agents include selective estrogen receptor modulators (SERMs) such as raloxifen, tamoxifen or lasoxifen.
• SERMs selective estrogen receptor modulators
• the HMG CoA reductase compound of the invention may also be employed in combination with a tyrosine kinase inhibitor such as disclosed in WO 2000/053605; the selective androgen receptor modulator suitable for use herein may be LGD-2226 (Ligand) ; the antiarrhythmic agents suitable for use herein include ⁇ -blockers as set out herein including sotalol and amioderome, calcium channel blockers as set out herein including verapamil, nifedipine, amlodipine- besylate, and diltiazem, which may also be used in combination with a debrillator device such as a pace maker; coenzyme Q sub. 10 such as disclosed in U.S. Patent No.
• a chondroprotective compound such as a polysulfated glycosaminoglycan (PSGAG) , glucosamine, chondroitin sulfate (CS) , hyaluronic acid (HA) , pentosan polysulfate (PPS) , doxycycline or minocycline, such as disclosed in EP 970694; a cyclooxygenase (COX) -2 inhibitor, such as celecoxib (Celebrex® (Searle) ) or rofecoxib (Vioxx® (Merck) ) or a glycoprotein Ila/IIIb receptor antagonist such as disclosed in WO 99/45913 and tirofiban or abciximab; a 5-HT reuptake inhibitor
• PSGAG polysulfated glycosaminoglycan
• CS chondroitin sulfate
• HA hyaluronic acid
• PPS pentosan polysul
• anti-atherosclerosis agents such as ACAT inhibitors and lipoxygenase inhibitors as described herein and phospholipase A-2 inhibitors such as S-3013 and SB-435,495 (which are also anti-inflammatory agents); anti-infective agents such as quinolones, for example, ciprofloxacin, ofloxacin, and Tequin® (Bristol- Myers Squibb) , macrolides such as erythromycin and clarithro ycin (Biaxin® (Abbott) ) , and azithromycin (Zithromax (Pfizer) ) ; or an immunosuppressant (for use in transplantations) such as cyclosporine, mycophenolate mofetil,
• antineoplastic agent refers to compounds which prevent cancer cells from multiplying.
• the antineoplastic agents used herein prevent cancer cells from multiplying by: (1) interfering with the cell's ability to replicate DNA, or (2) inducing apoptosis in the cancerous cells.
• antineoplastic agents which are suitable for use in combinations of this invention include, but are not limited to, microtuble-stabilizing agents such as the taxanes, for example, paclitaxel (also known as Taxol®) , docetaxel (also known as Taxotere®) , 7- O-methylthio- methylpaclitaxel (disclosed in U.S.
• C-4 methyl carbonate paclitaxel (disclosed in WO 94/14787)
• the epothilone such as epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-
• antineoplastic agents suitable for use in the method of the present invention include, but are not limited to, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, discodermolide, the pteridine family of drugs, diynenes, aromatase inhibitors, and the podophyllotoxins .
• Particularly useful members of those classes not previously mentioned include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6- mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, and the like.
• antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosfamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons, and interleukins .
• a pharmaceutical composition will be employed containing the compounds of structure I, with or without other cholesterol lowering agents, osteoporosis agents, Alzheimer's agents, antidiabetic agent (s) and/or antihyperlipidemic agent (s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent.
• the pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, such as pharmaceutically acceptable carriers, excipients, binders and the like.
• the compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, or they can be administered intranasally or in transdermal patches.
• Typical solid formulations will contain from about 0.1 to about 500 mg of a compound of formula I.
• the dose for adults is preferably between 0.5 and 1,000 mg per day, which can be administered in a single dose or in the form of individual doses from 1-4 times per day and also single dose once weekly (5 to 1000 mg) .
• a typical injectable preparation is produced by aseptically placing 250 mg of compounds of structure I into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
• Ph phenyl
• Boc tert-butoxycarbonyl
• Cbz carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
• DIPEA diisopropyl ethylamine
• TPAP tetrapropylammonium perruthenate
• NMM N-methyl morpholine
• n-BuLi n-butyllithium
• EDAC 3-ethyl-3' - (dimethylamino) propyl-carbodiimide hydrochloride (or 1- [ (3- (dimethyl) amino) propyl] ) -3- ethylcarbodiimide hydrochloride)
• HOBT or HOBT.H 2 0 1-hydroxybenzotriazole hydrate
• HOAT l-hydroxy-7-azabenzotriazole
• PyBOP reagent benzotriazol-1-yloxy-tripyrrolidino phosphonium hexafluorophosphate
• LiN(TMS) 2 Libis (trimethylsilyl) amide
• DIBAL diisobutylaluminum hydride
• DMPU 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (IH) -pyrimidinone
• NaHMDS sodium bis (trimethylsilyl) amide
• Red-AL sodium bis (2-methoxyethoxy) aluminum hydride
• a mixture of polyphosphoric acid (82.9 g) and dry o-xylene (30 ml) was heated to 105-110°C in an oil bath, treated with a solution of 4-phenoxybutyric acid (25 g, 0.137 mole) in dry o-xylene (110 ml) and stirred at 105- 110°C for 2 hours.
• the reaction mixture was cooled to room temperature over a 2-hour period, poured into ice- water (180 ml) , then extracted with ether (3 x 150 ml) .
• reaction mixture was cooled periodically with an ice-bath to keep the temperature around 35°C to 50°C After one hour, gas evolution had ceased and the reaction mixture was stirred at room temperature for 2h.
• the reaction mixture was cooled in an ice-bath, diluted with Et 2 0 (200 mL) , and treated with 1 N HCl with some ice to adjust to around pH 3.
• the reaction mixture was extracted with Et 2 0 (3 x 150 mL) .
• the reaction mixture was quenched at 0°C by the dropwise addition of glacial acetic acid (5 ml) and the resulting slurry was stirred at room temperature for another 5 minutes then poured slowly into an ammonium chloride solution (25%, 140 ml) .
• the bright yellow solution was extracted with ether (2 x 100 ml) and the combined organic extracts were washed with water (2 x 25 ml) and brine (25 ml) , dried (anhydrous Na 2 S0 4 ) , filtered, .evaporated to dryness and dried in vacuo to give the crude product mixture as a yellow oil (17.16 g) .
• Part C compound (22.515 g, 6.23 mmol) in dry THF (30 ml) was cooled to 0°C (ice-water bath) , treated dropwise with lithium aluminum hydride (1.0 M in THF; 12.5 ml, 12.5 mmol), stirred at 0°C for 30 minutes then at room temperature for 3 hours .
• the reaction mixture was cooled to 0°C, treated successively with water (0.5 ml), 15% ⁇ aOH (0.5 ml) and water (1.5 ml), stirred at room temperature for 5 minutes then diluted with ethyl acetate (50 ml) .
• Part F compound (2.29 g, 4.756 mmol) in dry THF (20 ml) was cooled to -78 °C, treated with 2.37 M n-butyllitium (2.41 ml, 5.71 mmol) and stirred at -78°C for 40 minutes.
• the solution was treated dropwise via cannula with a -78°C solution of Part A(l) compound (2.36 g, 9.15 mmol) in dry THF (10 ml), keeping both solutions at -78°C at all times.
• Part G compound 850 mg, 1.45 mmol
• dry dichloromethane (20 ml) was cooled to 0°C, treated with trifluoroacetic acid (1.85 ml, 24 mmol), stirred at 0°C for 5 minutes, then at room temperature for 4.5 hours .
• the reaction mixture was poured slowly into a 1 L flask containing ethyl acetate (300 ml) and saturated sodium bicarbonate (40 ml) , rinsing the flask with ethyl acetate (50 ml) .
• the mixture was stirred well and the phases separated, washing the organic phase with saturated sodium bicarbonate (25 ml) and brine (25 ml) .
• Part H compound 550 mg, 1.17 mmol in dry THF (10 ml) was treated with 1.0 N NaOH (1.46 ml; 1.46 mmol) and stirred at room temperature for 10 minutes.
• the reaction mixture was evaporated to dryness and the residual solid was dissolved in a mixture of water (8.7 ml) and 1.0 N sodium hydroxide (70 ul) .
• the solution was eluted on an SP207 column (Na+ form; 1.5" x 4"), eluting the column with water (200 ml), 10% CH 3 CN/H 2 0 (200 ml) , 20% CH 3 CN/H 2 0 (100 ml) and 50% CH 3 CN/H 2 0 (200 ml) .
• Example 1 Part E bromide (13.03 g, 0.027 mol, 1 equiv) and Ph 2 POEt (6.5 L, 0.0297 mol, 1.1 equiv) were heated at reflux in anhydrous toluene (200 mL) under an argon atmosphere.
• the reaction became a thick yet stirrable white mixture after about 10 min.
• the yellow reaction mixture was diluted with Et 2 0 (50mL) and washed with 0.5 ⁇ aq HCl, satd. aq NaHC0 3 , H 2 0, and satd. aq NaCl.
• the organic extract was dried over anhydrous Na 2 S0 4 , vacuum filtered and the ' filtrate concentrated by rotary evaporation in vaQUO to yellow oil. Vacuum distillation afforded the desired product as a light yellow oil (8.575 g, 0.0324 mol, 83%): bp 107-115°C (0.225 mm Hg) ;
• Example 1 Part A compound (7.824 g, 0.0482 mol, 1.5 equiv) in dry THF (6 mL) was added via cannula and the enolate allowed to generate over 1 hr at -78°C
• a solution of Part A compound (8.50 g, 0.0322 mol, 1 equiv) in dry THF (6 mL) was added via cannula and the resulting amber solution stirred at -78°C for 30 min, then at 0°C for 30 min.
• the reaction was quenched with glacial acetic acid (6 mL) , then poured into satd aq NH 4 C1.
• the Part D alcohol (3.066g, 8.437 mmol, 1 equiv), dissolved in dry CH 2 C1 2 (60 mL) under argon at 0°C, was treated by dropwise addition of a 1M solution of PBr 3 in CH 2 C1 2 (16.9 mL, 16.9 mmol, 2 equiv) .
• the reaction was stirred at rt for 30 min, at which time the reaction was recooled to 0°C and treated with satd aq NaHC0 3 (90 mL) .
• Example 1 A(l) aldehyde (0.566 g, 2.192 mmol, 1.2 equiv) in an oven-dried 100-mL flask (material previously chased with anhydrous toluene (3x5 mL) and dried in vacuo) under argon atmosphere was dissolved in dry THF (5 mL) and cooled to -78°C. The anion solution was added via cannula to the aldehyde solution over a period of 25 min, then the dark green- colored solution was stirred at -78°C for 1.5 hrs. The acetone/dry ice bath was then removed and the reaction allowed to slowly warm to room temperature; the initially green solution became an orange mixture.
• a SP207 Na- form resin column (1.9cm x 10cm bed) was prepared as follows : the resin was poured into a glass chromatography column equipped with fritted disc support, the resin was washed with satd aq NaHC0 3 (15 mL) , satd aq NaCl (15 mL) , and DI H 2 0 (100 mL, Milli-Q) . The residue was taken up in Milli-Q DI H 2 0 (5 mL) , applied to column, and eluted with Milli-Q DI H 2 0 (100 mL) , 10% AcCN/H 2 0 (60 mL) , and 25% AcCN/H 2 0 (125 mL) .
• Example 2 Part G compound 200 mg, 0.3403 mmol, 1 equiv was hydrogenated at 45 psi H 2 in anhydrous MeOH (30 mL) with 10% Pd-C (40 mg, 20 wt %) for 2 hrs.
• the catalyst was washed with small portions of MeOH and the filtrate was concentrated by rotary evaporation in vacuo.
• the residue was purified by Si0 2 flash chromatography
• Part A compound (258 mg, 0.4375 mmol) was dissolved in dry CH 2 C1 2 (5 mL) under argon, cooled to 0°C and treated with trifluoroacetic acid (0.5 mL) . Stirring was continued at room temperature for 7 hrs, at which time the reaction was complete by HPLC Saturated aqueous NaHC0 3 (25 mL) was added to the reaction, the reaction was diluted with EtOAc (100 mL) , and the layers separated. The organic was washed with saturated aqueous NaHC0 3 and saturated aqueous NaCl, then dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo .
• Part B compound (149 mg, 0.3133 mmol, 1 equiv) was dissolved in THF (3 mL) and IN aqueous NaOH (0.392 mL, 0.3916 mmol, 1.25 equiv) and stirred at room temperature for 30 min. The solvent was removed by rotary evaporation in vacuo and the residue was dried under high-vacuum.
• An SP207 resin column (1.9 cm x 10 cm ) was prepared as follows: resin was poured into a glass chromatography column equipped with fritted disc support and the resin was washed sequentially with saturated aqueous NaHC0 3 (15 mL) , saturated aqueous NaCl (15 mL) , and Milli-Q H 2 0 (100 mL) . The dried residue was taken up in Milli-Q H 2 0 (8 mL) and carefully applied to top of the column.
• the column was eluted with Milli-Q H 2 0 (100 mL) , 10% AcCN/ H 2 0 (60 mL) , 20% AcCN/ H 2 0 (60 mL) , and 25% AcCN/ H 2 0 (100 mL) .
• Product-containing fractions were combined and concentrated by rotary evaporation to a small volume, and transferred to a 40-mL lyophilization jar. The contents were frozen in acetone-dry ice bath and lyophilized.
• Phases are separated and the spent toluene phase is discarded.
• the pH of the aqueous phase is adjusted from ⁇ 0 to 4-5 with ION NaOH.
• Ethyl acetate 500 mL is added and the pH adjustment continued to 7-8.
• the phases are separated.
• the aqueous phase is extracted with additional ethyl acetate (2 x 500 mL) .
• the combined rich ethyl acetate solution is washed with water (3 x 250 mL) and concentrated under reduced pressure to ⁇ 465 mL. This solution is carried through to the next oxidation step.
• the rich ethyl acetate solution is charged from above into a three neck 1-L flask equipped with mechanical stirring, temperature controller, and addition funnel and cooled to 0-5°C.
• potassium bromide (1.53 g, 12.8 mmol)
• TEMPO 2,2,6,6- tetramethyl-1-piperidinyloxy
• the pH of NaOCl (sodium hypochlorite) solution (212.1 mL) is adjusted to ⁇ 9.1 and added to the slurry at a rate such that the temperature remained at 0-5°C Stirring is continued at 0-5°C until the reaction is complete as determined by HPLC.
• the aqueous phase is extracted with EtOAc (2 x 200 mL) .
• the combined rich organic phase is washed with a 1:1 solution of sat. aq. Na 2 S 2 0 3 (sodium thiosulfate) (75 mL) and water (75 mL) followed by wash of the rich organic phase with IN NaOH (250 mL) .
• the rich organic phase is washed with water (250 mL) and concentrated to ⁇ 100 mL under reduced pressure. Isopropanol (IPA) (400 mL) is added and the resulting mixture is heated to reflux (80-85°C) .
• the solution is distilled to a volume of -250 mL.
• Kaneka alcohol (12) (Scheme 6) (10.0 g, 38.41 mmol), methylene chloride (100 mL) , and triethylamine (11.75 mL, 84.51 mmol) and cooled to -30°C.
• Triflie anhydride (7.11 mL, 42.25 mmol) was added via a syringe at a rate to maintain the temperature at -35 to -25°C, ⁇ 15 min.
• IPA 150 mL
• IPA 150 mL
• IPA 150 mL
• the solution was cooled to 0-5°C.
• a solution of (NH 4 ) 6 M0 7 0 24 »4H 2 0 (ammonium heptamolybdate tetrahydrate) (4.75 g, 3.84 mmol) in 30% H 2 0 2 (hydrogen peroxide) was added dropwise during ⁇ 15 min, maintaining the temperature of the solutin at 0-5°C
• the conversion of sulfide to sulfone was monitored by HPLC -24 h. After completion of the reaction, methylene chloride was distilled out.
• the pot temperature was maintained at not more than 25°C
• the crystal slurry was distilled to a volume of -230 mL with IPA and the resulting slurry was stirred for at least 1 h at 20-22°C.
• the solid was collected by vacuum filtration, the cake washed with IPA/water (4:1, 25 mL) followed by drying under vacuum at 40°C to constant weight affording 12.8 g (74%) of the title sulfone as a white crystalline solid.
• Example 27 pyridine derivative and the Example 28 sulfone are employed to prepare the title compound.
• An example of a typical preparation of the Example 29 compound is set out below.
• Example 27 pyridine derivative (18) (5 g, 13.9 mmol)
• Example 28 sulfone (16) (6.9 g, 15.3 mmol)
• THF 75 mL
• the stirred solution is cooled to -74 to -78°C .
• a 1M solution of LiHMDS (lithium bis (trimethylsilyl) amide) (15.3 mL, 15.3 mmol) in THF is charged at a rate such that the temperture remained between -70 and -78°C.
• the reaciton mixture is warmed to —45°C over -15 minutes.
• the stirred reaction is quenched at -70°C by slow addition of sat. aq. NH 4 C1 (7.5 mL) solution and water (38 mL) .
• the dry ice bath is removed and the solution is warmed to 20-25°C from the reaction mixture.
• Ethyl acetate (50 mL) is added, the mixture agitated, and layers separated.
• the organic layer is washed with saturated sodium bicarbonate solution (2 x 38 mL) followed by brine (25 mL) and concentrated to a volume of 50 mL.
• Acetonitrile (50 mL) is added and the solution is concentrated to a volume of 50 mL. This step is repeated.
• Example 29 compound is employed to prepare the title compound in the form of the sodium salt.

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